Stop codon at arginine 586 is the prevalent nephronopthisis type 1 mutation in Italy

Nephronophthisis (NPHP) is an autosomal recessive disease with prevalent renal manifestations, characterized by occasional cysts in medulla and severe tubulo-interstitial fibrosis, evolving to end-stage renal failure [1]. It represents the most frequent cause of uraemia in children, with major clinical, physiological and social consequences including high costs for substitutive approaches and renal transplant. NPHP is a clinical and genetic heterogeneous disease with at least five genes (NPHP1–5) identified and variable extra-renal manifestations [2–6]. Retinal dysfunction constituting Senior Loken syndrome (SLS1–5) is the most common association [1]. Other organ defects identify specific subsets such as liver fibrosis in NPHP3 and situs inversus in NPHP2. NPHP1 [OMIM #256100] represents the most frequent variant. On a molecular basis, the large majority of patients with NPHP1 present a large homozygous deletion [7] at 2q13 [NPHP1-del] that includes nephrocystin, the NPHP1 gene [2,8]. Patients with NPHP1 gene mutations are rare. A revision of the literature reveals only one case with compound heterozygous mutation, while less uncommon is the combination of [NPHP1-del] with a point mutation of NPHP1 ‘in trans’ [2,8–13], which has been reported in 11 cases (Table 1). Hildebrandt et al. [12] calculated the probability of compound heterozygous NPHP1 mutation in 1 out of 10. Based on these frequencies, molecular analysis of NPHP1 is indicated only in patients with heterozygous [NPHP1-del] [12]. We report here the final results of the screening for NPHP1 mutations in patients with clinical NPHP, for whom the presence of homozygous [NPHP1-del] had been previously excluded. Four cases with NPHP1 mutations were found, one with compound heterozygous mutation and three with an association with [NPHP1-del] that challenges the concept of rarity and suggests that mutation analysis be done in patients with clinical signs of NPHP.